CAlcium and VAsopressin Following Injury Early Resuscitation (CAVALIER) Trial (CAVALIER)

• ClinicalTrials.gov Identifier: NCT05958342
• Recruitment Status: Not yet recruiting
• First Posted: July 24, 2023
• Sponsor: Jason Sperry
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Jason Sperry, University of Pittsburgh

Study Description

Brief Summary:

The CAlcium and VAsopressin following Injury Early Resuscitation (CAVALIER) Trial is a proposed 4 year, double-blind, mutli-center, prehospital and early in hospital phase randomized trial designed to determine the efficacy and safety of prehospital calcium and early in hospital vasopressin in patients at risk of hemorrhagic shock.

Condition or disease	Intervention/treatment	Phase
Trauma; Hemorrhage	Drug: Calcium Gluconate; Drug: Vasopressin; Drug: saline placebo	Phase 2

Detailed Description:

Resuscitation strategies for the acutely injured patient in hemorrhagic shock have evolved. Patients benefit from receiving less crystalloid in favor of blood transfusions with balanced ratios of plasma and platelets or whole blood resuscitation. These resuscitation practices are termed Damage Control Resuscitation and have been incorporated into resuscitation protocols in Level I trauma centers across the country. Damage Control Resuscitation represents standard practice for military and civilian trauma. Despite these changes, deaths from traumatic hemorrhage continue to occur in the first hours following trauma center arrival, underscoring the importance of early, novel interventions.

Hypocalcemia following traumatic injury is exceedingly common following severe traumatic injury in patients at risk of hemorrhagic shock. During hemorrhagic shock resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted. Citrate containing transfusion products are known to further reduce calcium levels through chelation during trauma resuscitation. Hypocalcemia has consistently been shown to be independently associated with the risk of large volume blood transfusion and mortality. Current management practices include calcium replacement during the in hospital phase of care in patients receiving blood products. Early calcium replacement in patients at risk of hemorrhage and hypocalcemia may mitigate coagulopathy, maintain hemostasis, improve hemodynamics and outcomes, and may reduce complications attributable to hemorrhagic shock.

Arginine vasopressin is a physiologic hormone released by the posterior pituitary in response to hypotension and is commonly used as a vasopressor for critically ill patients for the treatment of hypotension due to multiple causes including sepsis. Prolonged hemorrhagic shock has the potential to alter systemic vasomotor tone which can progress to refractory/recalcitrant hypotension. Patients receiving resuscitation for hemorrhage are at risk of vasopressin deficiency. Vasopressin may improve hemostasis by enhancing platelet function and augmenting clot formation. Vasopressin infusion soon after injury in patients in hemorrhagic shock has been demonstrated to be safe and result in a reduction in blood transfusion requirements and a lower incidence of deep venous thrombosis.

Whole blood, red cells, and blood components are a precious and limited resource. Trauma resuscitation adjuncts such as early calcium and vasopressin may provide benefit when transfusion products are limited and may provide additional benefit even when transfusion capabilities remain robust. Due to their action on coagulation and hemodynamic cascades in the injured patient, these resuscitation adjuncts have the potential to interact and provide additive benefit to the injured patient. However, safety and efficacy of prehospital calcium and early in hospital vasopressin remain inadequately characterized. Enrolled patients may participate in the prehospital phase (calcium), in-hospital phase (vasopressin), or both. The aims of the CAlcium and VAsopressin following Injury Early Resuscitation (CAVALIER) trial are to determine the efficacy and safety of prehospital calcium supplementation and early in hospital vasopressin infusion as compared to standard care resuscitation in patients at risk of hemorrhagic shock and to appropriately characterize any additive effect of both resuscitation adjunct interventions.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1050 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: permuted block design
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: CAlcium and VAsopressin Following Injury Early Resuscitation (CAVALIER) Trial
• Estimated Study Start Date: July 2024
• Estimated Primary Completion Date: March 2027
• Estimated Study Completion Date: March 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Prehospital Intervention Arm; 1 gram calcium gluconate provided intravenously over approximately 2-5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed	Drug: Calcium Gluconate; 1 gram calcium gluconate provided intravenously over approximately 2-5 minutes
Placebo Comparator: Prehospital Control Arm; Identical volume saline placebo to prehospital intervention arm provided intravenously over approximately 2-5 minutes, initiated prior to trauma bay arrival and infused to completion following arrival if needed	Drug: saline placebo; saline placebo volume matched to prehospital or in hospital phase
Experimental: Early In-Hospital Intervention Arm; 4 unit vasopressin bolus followed by a vasopressin infusion at 0.04 U/min for eight hours, initiated within approximately two hours of hospital arrival	Drug: Vasopressin; 4 unit vasopressin bolus followed by vasopressin infusion at 0.04 U/min for eight hours
Placebo Comparator: Early In-Hospital Control Arm; volume matched saline bolus followed by volume matched normal saline placebo infusion for eight hours initiated within approximately two hours of arrival	Drug: saline placebo; saline placebo volume matched to prehospital or in hospital phase

Outcome Measures

Primary Outcome Measures :

1. Number of participants with 30-day mortality [ Time Frame: from randomization to death or 30 days, whichever comes first ]
   all cause mortality within 30 days

Secondary Outcome Measures :

1. Number of participants with 6-hour mortality [ Time Frame: from randomization to death or 6 hours, whichever comes first ]
   all cause mortality within 6 hours
2. Number of participants with 24-hour mortality [ Time Frame: from randomization to death or 24 hours, whichever comes first ]
   all cause mortality within 24 hours
3. Number of participants with In-hospital mortality [ Time Frame: In hospital mortality from time of randomization to death or 30 days, whichever comes first ]
   death prior to hospital discharge
4. Number of participants with Death from hemorrhage [ Time Frame: from randomization to death or 30 days, whichever comes first ]
   Death from hemorrhage adjudicated by the site investigator
5. Number of participants with Death from brain injury [ Time Frame: from randomization to death or 30 days, whichever comes first ]
   Death from brain injury adjudicated by the site investigator
6. Blood and blood component transfusion requirements in the initial 6 hours [ Time Frame: from randomization to 6 hours ]
   number of units transfused and type
7. Blood and blood component transfusion requirements in the initial 24 hours [ Time Frame: from randomization to 24 hours ]
   number of units transfused and type
8. Incidence of Multiple Organ Failure (MOF) [ Time Frame: Scores determined daily until up to Day 7 or ICU discharge, whichever comes first ]
   Evaluated via the Denver Post injury Multiple Organ Failure Score, characterized as an incidence rate (percentage) and as MOF free days. Patients never admitted to ICU or with length of stay less than 48 hours will have a score of 0. A summary Denver score of >3 will be classified as MOF.
9. Incidence of nosocomial infection [ Time Frame: from randomization to death or 30 days ]
   Utilizing the CDC criteria for diagnosis of hospital acquired pneumonia and blood stream infection
10. Time to hemostasis [ Time Frame: hospital arrival to 4 hours ]
    Determined by ability to reach nadir transfusion requirement of 1 unit of red blood cells in a 60 minute period in the first 4 hours following arrival. In the absence of ability to obtain hemostasis within the first 4 hours, the patient will be designated "non-hemostasis"
11. Incidence of coagulopathy by thromboelastography (TEG) [ Time Frame: within 4 hours of arrival plus or minus 12 ]
    TEG date collected only when obtained as part of clinical
12. Incidence of coagulopathy by thromboelastography (TEG) [ Time Frame: within 24 hours of arrival plus or minus 12 ]
    TEG date collected only when obtained as part of clinical
13. ICU free days [ Time Frame: From hospital arrival to death or 30 days ]
    number of days the patient is alive and not admitted to ICU subtracted from 30
14. Hospital free days [ Time Frame: From hospital arrival to death or 30 days ]
    number of days the patient is alive and not admitted to hospital subtracted from 30

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Prehospital Phase:

Injured patients at risk of hemorrhagic shock being transported from scene or referral hospital to a participating CAVALIER trial site who meet the following criteria:

1A. Systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) at scene, at outside hospital, or during anticipated transport to a participating CAVALIER trial site

OR

1B. Systolic blood pressure ≤ 70mmHg at scene, at outside hospital, or during anticipated transport to a participating CAVALIER trial site

Early In-Hospital Phase:

Injured patients at a participating CAVALIER trial site at risk of hemorrhagic shock who meet the following criteria:

1A. Systolic blood pressure ≤ 90mmHg and tachycardia (HR ≥ 108) at scene, at outside hospital, during transport, or in emergency department of a participating CAVALIER trial site

OR

1B. Systolic blood pressure ≤ 70mmHg at scene, at outside hospital, during transport, or in emergency department of a participating CAVALIER trial site

AND

2.Blood/blood component transfusion initiated in prehospital setting or deemed clinically indicated within 60 minutes of arrival at the enrolling trauma center

AND 3. Clinical team deems Operating Room for major hemorrhage control procedure (e.g., laparotomy, thoracotomy, vascular exploration or extremity amputation) indicated within 60 minutes of arrival at the enrolling trauma center

AND

4. Anticipated admission to intensive care unit (ICU)

Exclusion Criteria:

1. Wearing NO CAVALIER opt-out bracelet
2. Age > 90 or < 18 years of age
3. Isolated fall from standing injury mechanism
4. Known prisoner
5. Known pregnancy
6. Traumatic arrest with > 5 minutes of CPR without return of vital signs
7. Brain matter exposed or penetrating brain injury
8. Isolated drowning or hanging victims
9. Objection to study voiced by subject or family member at the scene or at the trauma center
10. Inability to obtain IV access

Contacts and Locations

Contacts

Contact: Jason Sperry, MD; 4128028270; sperryjl@upmc.edu

Locations

United States, Pennsylvania

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

Contact: Jason Sperry, MD 412-647-3065 sperryjl@upmc.edu

Sponsors and Collaborators

Jason Sperry

United States Department of Defense

Investigators

• Principal Investigator: Jason Sperry, MD; University of Pittsburgh

More Information

• Responsible Party: Jason Sperry, Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT05958342
• Other Study ID Numbers: STUDY23040043; W81XWH-6-D-0024 ( Other Grant/Funding Number: Department of Defense )
• First Posted: July 24, 2023
• Last Update Posted: April 23, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified data may be shared with the funding agency as well as other researchers upon request to the Principal Investigator
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: Data will become available after publication of the primary manuscript
• Access Criteria: Requests for data will be submitted in writing and reviewed by the Principal Investigator

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jason Sperry, University of Pittsburgh:

hemorrhagic shock; trauma; calcium gluconate; vasopressin

Additional relevant MeSH terms:

Hemorrhage; Pathologic Processes; Vasopressins; Arginine Vasopressin; Calcium; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Agents; Natriuretic Agents